Expression of human glutathione S-transferases in Saccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil

Abstract

Adaptation and resistance to chemicals in the environment is a critical part of the evolutionary process. As a result, a wide variety of defence systems that protect cells against chemical insult have evolved. Such chemical resistance mechanisms appear to play a central role in determining the sensitivity of human tumours to treatment with chemotherapeutic drugs. The glutathione S-transferases (GST) are important detoxification enzymes whose over-expression has been associated with drug-resistance. In order to evaluate this possibility we have expressed the human Alpha-class and Pi-class GST cDNAs that encode GST B1B1 and GST pi in the yeast Saccharomyces cerevisiae. The expression of GST B1B1 or GST pi resulted in a marked reduction in the cytotoxic effects of chlorambucil, a bifunctional alkylating agent, and an anthracycline, adriamycin. These data provide direct evidence that the over-expression of GST in cells can confer resistance to anticancer drugs.

The role of glutathione-S-transferase in anti-cancer drug resistance

“…Saccharomyces cerevisiae, where a significant resistance to chlorambucil and doxorubicin (eight-and 16-fold, respectively) was reported in cells transfected with mammalian GST isozymes (Black et al, 1990). Interpretation of these earlier data did not take into account the more recent observations on the involvement of GSTs in kinase regulation.…”

Predictive Potential of Glutathione S-Transferase Polymorphisms for Prognosis of Osteosarcoma Patients on Chemotherapy

“…Anticancer drugs that have been shown to be substrates for GSTs are, for example, chlorambucil, melphalan, cyclophosphamide metabolites, and steroids (Yuan et al, 1991;Listowsky, 1993;Tew, 1994). Indirect evidence for a role of GSTs in modulating drug effects through deactivation of drug-generated hydroperoxides or other reactive oxygene species exists for adriamycin, mitomycin C, carboplatin, and cisplatin (Black et al, 1990;Nakagawa et al, 1990;Tew, 1994).…”

A study of ethacrynic acid as a potential modifier of melphalan and cisplatin sensitivity in human lung cancer parental and drug-resistant cell lines

“…The transfection of genes encoding for human pi and alpha class GSTs into yeast cells has been shown to confer resistance to chlorambucil (Black et al, 1989). Human GST pi genes have also been transfected into mammalian cells and found to confer resistance to known substrates of this class, such as ethacrynic acid, but not to anti-tumour agents such as cisplatin and melphalan (Moscow et al, 1989).…”